# Mechanism for endogenous retroelements to mimic ancient exogenous identities in aging and diseased human tissue

> **NIH NIH DP2** · BOSTON CHILDREN'S HOSPITAL · 2020 · $2,655,000

## Abstract

Project Summary
The goal of this proposal is to investigate retrotransposons as a significant source of immunogenic molecules
in aging and diseased human tissues. This is an important but understudied area of human genomic research.
I have pioneered methods to detect retrotransposons from genome sequences to determine their role in the
human brain and in cancer. In this application, I will build on my earlier success to develop other innovative
methods and apply them to the study of immunological impact of retrotransposons. Specifically, this proposal is
to discover the origins of retrotransposon-derived molecules (RDMs) and the functional consequences of
RDMS in pathogenesis to provide a mechanistic basis for novel therapeutics or biomarkers. Retrotransposons
have been recognized as important to evolutionary processes and to the causes of Mendelian disorders;
however, we propose a new perspective on these endogenous retroelements, suggesting that these normally
suppressed domesticated agents are reactivated, producing RDMs that may be considered as foreign
molecules, thus causing immunologic responses mimicking their ancient exogenous identities, especially in
aging and diseased tissue. Increasing evidence, including our own work, shows that with aging, there is an
increasing rate of somatic retrotransposon mobilization and other mutations, suggesting a corresponding
increased load of various forms of RDMs (e.g., cytosolic ss/dsRNA, cDNA, and neo-peptides) contributing to
pathophysiology. In particular, we focus on scrutinizing retrotransposon-derived RNA that produces neo-
peptides caused by altered splicing (e.g., exonization or gene-retrotransposon fusion) or by mutations in
protein-coding sequences of retrotransposons. Building upon my expertise in retrotransposons, somatic
mutations, and splicing using a genomic and single-cell approach, this study will build a methodological
framework to reveal the landscape of age-dependent retrotransposon activity and the abundance of RDMS in
various human tissues as the foundation upon which to achieve further findings in this nascent field of inquiry.
It will also characterize RDMs associated with molecular/pathological/clinical parameters and underlying
mechanisms. This project will support my long-term research goal of defining the role of retrotransposons in
human health and disease to provide the basis for effective therapeutics to improve human life and health.

## Key facts

- **NIH application ID:** 10002836
- **Project number:** 1DP2AG072437-01
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Alice Eunjung Lee
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,655,000
- **Award type:** 1
- **Project period:** 2020-09-30 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10002836

## Citation

> US National Institutes of Health, RePORTER application 10002836, Mechanism for endogenous retroelements to mimic ancient exogenous identities in aging and diseased human tissue (1DP2AG072437-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10002836. Licensed CC0.

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